title: Catalytic activity of the caspase-8-FLIP(L) complex inhibits RIPK3-dependent necrosis.
abstract: Caspase-8 has two opposing biological functions--it promotes cell death by triggering the extrinsic pathway of apoptosis, but also has a survival activity, as it is required for embryonic development, T-lymphocyte activation, and resistance to necrosis induced by tumour necrosis factor-α (TNF-α) and related family ligands. Here we show that development of caspase-8-deficient mice is completely rescued by ablation of receptor interacting protein kinase-3 (RIPK3). Adult animals lacking both caspase-8 and RIPK3 display a progressive lymphoaccumulative disease resembling that seen with defects in CD95 or CD95-ligand (also known as FAS and FASLG, respectively), and resist the lethal effects of CD95 ligation in vivo. We have found that caspase-8 prevents RIPK3-dependent necrosis without inducing apoptosis by functioning in a proteolytically active complex with FLICE-like inhibitory protein long (FLIP(L), also known as CFLAR), and this complex is required for the protective function.
authors.affiliation: Dept. of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Oberst
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Dillon
authors.forename: Ricardo
authors.initials: R
authors.lastname: Weinlich
authors.forename: Laura L
authors.initials: LL
authors.lastname: McCormick
authors.forename: Patrick
authors.initials: P
authors.lastname: Fitzgerald
authors.forename: Cristina
authors.initials: C
authors.lastname: Pop
authors.forename: Razq
authors.initials: R
authors.lastname: Hakem
authors.forename: Guy S
authors.initials: GS
authors.lastname: Salvesen
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Green
mesh_terms: D000818:Animals; D017209:Apoptosis; D055162:Biocatalysis; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism*; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism*; D061945:Caspase Inhibitors; D002460:Cell Line; D005260:Female; D008297:Male; D051379:Mice; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism; D009336:Necrosis; D010641:Phenotype; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015843:Serpins / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000494:pharmacology; D014764:Viral Proteins / Q000494:pharmacology; D019014:fas Receptor / Q000172:deficiency / Q000378:metabolism
chemical_list: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D061945:Caspase Inhibitors; C506387:Cflar protein, mouse; D046912:Multiprotein Complexes; D015843:Serpins; D014409:Tumor Necrosis Factor-alpha; D014764:Viral Proteins; D019014:fas Receptor; C074641:interleukin-1beta-converting enzyme inhibitor; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C485615:Ripk3 protein, mouse; D053181:Caspase 8